The invention relates to a semisolid aqueous pharmaceutical composition containing tapentadol or a physiologically acceptable salt thereof.
Tapentadol is a centrally-acting analgesic with a dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor (cf. T. M. Tzschentke et al., Drugs of the future, 2006, 12, 1053-1061). Solid oral dosage forms of tapentadol are known from the prior art, e.g. WO 02/67651, WO 03/035053, WO 2006/002886, WO 2007/128412, WO 2007/128413, WO 2008/110323, WO 2009/092601, WO 2009/067703, and US2010-272815. WO 2008/110323 discloses a composition for parenteral administration of 20 g (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride in 1 L water for injection purposes which has been isotonized by addition of NaCl.
However, solid oral dosage forms containing tapentadol are not satisfactory in every respect and there is a demand of pharmaceutical formulations which have advantages compared to the known solid oral dosage forms.
For instance, the pain may be caused by a topical effect that does not require systemic treatment. In this case, systemic side effects may be avoided when tapentadol is applied topically and/or locally. Typically, the drug may be applied directly to the source of pain in a high dosage, thereby keeping the burden to entire organism to a minimum. Consequently, there is a demand of pharmaceutical formulations containing tapentadol for topical and/or local administration.
The stability of the active ingredient in the final product is a primary concern to the formulator. In general, drug substances are less stable in aqueous media than solid dosage forms, and it is important to properly stabilize and preserve liquid aqueous formulations such as solutions, suspensions, and emulsions. Acid-base reactions, acid or base catalysis, oxidation, and reduction can occur in these products. These reactions can arise from drug substance-ingredient interactions, ingredient-ingredient interactions or container-product interactions. For pH sensitive compounds, any of these interactions may alter the pH and may cause precipitation.
Oxidative labile drug substances or vitamins, essential oils, and almost all fats and oils can be oxidized by auto-oxidation. Such reactions can be initiated by heat, light, peroxides, or other labile compounds or heavy metals such as copper or iron.
The effect of trace metals can be minimized by using chelating agents such as EDTA. Antioxidants may retard or delay oxidation by rapidly reacting with free radicals as they are formed (quenching). Common antioxidants include propyl, octyl and dodecylesters of gallic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, sodium ascorbate, monothioglycerol, potassium or sodium metabisulfite, propionic acid, propyl gallate, sodium bisulfite, sodium sulfite, and the tocopherols or vitamin E.
In addition to stabilization of pharmaceutical preparations against chemical and physical degradation, liquid and semisolid preparations, particularly multiple dose preparations, must usually be protected against microbial contamination. In contrast to solid preparations, aqueous solutions, syrups, emulsions, and suspensions often provide excellent growth media for microorganisms such as molds, yeast, and bacteria (e.g. Pseudomonas Aeruginosa, E. Coli, Salmonella spp., Staphylococcus aureus, Candida albicans, Aspergillus niger). Contamination by these microorganisms may occur during manufacturing or when a dose is taken from a multiple dose formulation. Growth of the microorganisms occurs when a sufficient amount of water is present in the formulation. Biphasic systems of the O/W-type are especially prone to be excellent breeding grounds for microorganisms.
Ophthalmic and injectable preparations are typically sterilized by autoclaving or filtration. However, many of them require the presence of an antimicrobial preservative to maintain aseptic conditions throughout their stated shelf life, specifically for multiple dose preparations.
When a preservative is required, its selection is based upon several considerations, in particular the site of use whether internal, external or ophthalmic (for further details it can be referred to e.g. Remington, The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005).
Many liquid and semisolid formulations, particularly multiple dose formulations and/or O/W-formulations, contain parabens as preservatives, e.g. methyl paraben (methyl-4-hydroxybenzoate) and propyl paraben (propyl-4-hydroxybenzoate). For example, in the Federal Republic of Germany semi-solid formulations containing analgesics such as ibuprofen and parabens are commercialized under the trademarks: Dolgit®, Ibutop® and Elacur®.
Because of the number of excipients and additives in pharmaceutical formulations, it is recommended all the ingredients be listed on the container to reduce the risks that confront hypersensitive patients when these products are administered.
Other commercialized pharmaceutical formulations contain sorbic acid or its potassium salt (e.g. Mobilat®) or benzalkonium chloride as preservative. Recently, side effects resulting from mucosal damage caused by benzalkonium chloride and potassium sorbate were reported (cf. C. Y. Ho et al., Am J Rhinol. 2008, 22(2), 125-9). As far as hypersensitivity reactions of preservatives in topical ophthalmic therapies are concerned, quaternary ammoniums (benzalkonium chloride) are commonly associated with irritant toxic reactions whereas the organomercurials (thimerosal) and the alcohols (chlorobutanol) have high associations, respectively, with allergic responses (cf. J. Hong et al., Curr Opin Allergy Clin Immunol. 2009, 9(5), 447-53). Parabens have been implicated in numerous cases of contact sensitivity associated with cutaneous exposure (cf. M. G. Soni et al., Food Chem. Toxicol. 2001, 39(6), 513-32) and have been reported to to exert a weak estrogenic activity (cf. S. Oishi, Food Chem. Toxicol. 2002, 40(12), 1807-13 and M. G. Soni et al., Food Chem. Toxicol. 2005, 43(7), 985-015).
Due to these undesired side effects of known preservatives, it is desirable to provide pharmaceutical compositions for topical and/or local administration that exhibit a sufficient shelf-life in the absence of preservatives or at least in the presence of comparatively low quantities thereof.